Multivalent pneumococcal vaccines can increase the transmissibility and virulence of non-vaccine...

Multivalent pneumococcal vaccines can increase the transmissibility and virulence of non-vaccine strains

Eleanor Watkins, Caroline Buckee, Bridget Penman, Martin Maiden, Sunetra Gupta

Methods for Mathematical and Empirical Analysis of Microbial Communities Isaac Newton Institute for Mathematical Sciences, Cambridge

28th October 2014

Streptococcus pneumoniae disease and

control

Developing a model of

pneumococcal population structure

Simulating vaccination

INI, Cambridge | 28th October 2014 | [email protected]

Nasopharynx

Streptococcus pneumoniae• Gram Positive• Carried in nasopharynx• Invasive infections: pneumonia, meningitis, sepsis• 1.6 million deaths annually


capsule


Serotypes and Vaccines

• >95 capsule types

• only ~15 cause most disease globally

•Design a vaccine which targets the most virulent serotypes

Heptavalent Pneumococcal Conjugate Vaccine (PCV7)• 4, 6B, 9V, 14, 18C, 19F, and 23F


Vaccine Induced Strain Replacement


Miller et al. (2011) Herd immunity and serotype replacement 4 years after seven-valent pneumococcal conjugate vaccination inEngland and Wales: an observational cohort study. Lancet Infect Dis.


All disease

Vaccine type disease

Non vaccine type disease

PCV7



Previous frameworks:

• Strong competition between strains

• Vaccination releases competition

• Inter-strain competitive interactions:> Immunological competition> Ecological competition


Lipsitch (1998) Vaccination against colonizing bacteria with multiple serotypes. PNAS. 94 6571Cobey & Lipsitch (2012) Niche and Neutral Effects of Acquired Immunity Permit Coexistence of Pneumococcal Serotypes. Science 335: 1576.


Previous frameworks:

• Strong competition between strains

• Vaccination releases competition

• Inter-strain competitive interactions:> Immunological competition> Ecological competition


Antigens

Virulence

Metabolism

Antigens

Virulence

MetabolismCapsule

Pili (type I and II)Pneumolysin variants

CarbohydrateAmino acid

LipidNucleotideTransport

Antigens

Virulence

MetabolismCapsule




Antigenic Type (AT)

Metabolic Type (MT)

Virulence Type (VT)

a Antigenic Type (AT)

Antigens

Virulence

Metabolism




a,b,c

Immunological competition

+ -Cost

Ecological competition

1, 2, 3

1>2>3

Ecologicalcompetition

Antigenic Type (AT)

Metabolic Type (MT)

Virulence Type (VT)

a Antigenic Type (AT)

a

a1+

+


a1+

a1-

b3-

b2-

a2-c1-

b1-

b3+

a3+c3+

c2+

b2+

a2+

c1+

b1+c3-

c2-a3-


a1

b2

c3


a1

b2

c3

Multi locus sequence typing (MLST)

Sequence type (ST)

ST

Sero

type

Bruggemann et al. (2003). Clonal Relationships between Invasive and Carriage Streptococcus pneumoniae and Serotype- and Clone-Specific Differences in Invasive Disease Potential. JID. 187:1424.

• Non-overlapping combinations of antigenic and metabolic types

• Only a minority of strains cause invasive disease, associated with the fittest metabolic types.

-

+

-


Metabolic Analysis of Pneumococcal Genomes• 616 pneumococcal genomes from Massachussetts• Identified all loci involved with metabolism and transport (890 in total)• Analysed allelic diversity of each metabolic/transport locus (Genome Comparator)

Locus 1

IsolatesAllele numbers

Locus 2Locus 3Locus 4

Croucher et al. (2013). Population genomics of post-vaccine changes in pneumococcal epidemiology. Nature Genetics.

www.pubmlst.orgJolley & Maiden (2010). BIGSdb: Scalable analysis of bacterial genome variation at the population level. BMC Bioinformatics 11:595


Vaccination


A B C

2 3

Vaccination could lead to increases in transmissibility and virulence

_ _

Vaccine Induced Metabolic Shift

Antigenic type

Metabolic type

Virulence type


Metabolic Shift in S. pneumoniae: Serotype 19A

Vaccine serotype 4

Vaccine serotype 19F

Non vaccine serotype 19A

Beall et al (2010) Shifting Genetic Structure of Invasive Serotype 19A Pneumococci in the United States. JID. 203:1360.

United States


Metabolic Shift in S. pneumoniae at the genomic level

19A (ST199)

19F(ST320) 19A

Vaccination


Virulence Shift in S. pneumoniae

Type I and II Pili

• Mediate adhesion to host cells

• Present in 30% (TI) and 16% (TII) of invasive pneumococci

• Bind to host extra-cellular matrix

• Interference between piliated strains and Staphylococcus aureus

Regev-Yochay et al (2009) The pneumococcal pilus predicts the absence of Staphylococcus aureus co-colonization in pneumococcal carriers. Clin. Inf. Dis. 15: 760.



Type I Pili

Regev-Yochay et al (2010) Re-emergence of the Type I Pilus among Steptococcus pneumoniae isolates in Massachusetts, USA. Vaccine. 5: 28. 155.

Increase in Type I pili among NVT strains (9% -> 30%)Role of ecological competition?



Type II Pili

Zahner et al (2010) Increase in Pilus Islet 2–encoded Pili among Streptococcus pneumoniae Isolates, Atlanta, Georgia, USA. Emerging Infectious Diseases. 16: 155.

Increase in Type II pili among 19A strains (1.5% -> 40%)


Summary

• Multilocus models allow us to examine different types of competition acting on different loci.

• Model predicts non-overlapping associations between antigenic and metabolic types, with a minority causing disease.

• Vaccination can lead to the emergence of the fittest metabolic type and high virulence trait with a non-vaccine serotype.

• Vaccine-induced metabolic shift can be observed at the whole genome level.

• Rapid increases have been observed in pilins in non-vaccine serotypes.

c


Acknowledgements

Professor Sunetra GuptaDr Bridget PenmanDr Caroline BuckeeProfessor Martin Maiden


Princeton University | 10th October 2014 | [email protected]

Effects of Cross-Immunity

Vaccination

Weak vaccine-induced cross-immunity

No vaccine-induced cross-immunity

Multivalent pneumococcal vaccines can increase the transmissibility and virulence of non-vaccine...

Documents

Transcript of Multivalent pneumococcal vaccines can increase the transmissibility and virulence of non-vaccine...